Pathophysiology

Normal haematopoiesis occurs within bone marrow; in adults almost exclusively within the pelvis⁷. All cells derive from the pluripotent haematopoietic stem cell and the first step is to transform into either a lymphoid or myeloid stem cell. From this point, there is stepwise maturation until the development of mature cells such as neutrophils or monocytes⁷.

This diagram shows the stepwise maturation of normal blood cells. In acute leukaemias, there are errors at an early stage in this process which proliferate. In chronic leukaemias, there is large-scale proliferation of more mature cells.

Acute leukaemia is caused by the uncontrolled proliferation of immature leukocytes, leading to high numbers of circulating blast cells (immature white cells).

Cells proliferate by mitosis. Mitosis is regulated by multiple proteins which arrest proliferation in the presence of defective DNA⁸. Dysfunction of these regulatory proteins, due to a genetic mutation, leads to uncontrolled proliferation and malignancy. Mutations are ordinarily acquired, but can also be inherited causing specific familial syndromes⁸.

Mutations occur via large-scale changes to the underlying DNA (such as chromosomal translocations or chromosomal deletions) or small-scale changes such as point mutations⁸. A well-known mutation is the Philadelphia Chromosome; a translocation between chromosomes 9 and 22 leads to an abnormal tyrosine kinase (BCR-ABL1) which leads to uncontrolled cellular proliferation⁸. Identifying specific mutations can have both diagnostic and prognostic significance in acute leukaemia.

The reason mutations occur is poorly understood, however known risk factors include:⁸

1. Previous haematological disorder – such as myelodysplastic syndrome, myelofibrosis, chronic myeloid leukaemia
2. Inherited conditions involving defects in normal DNA function – such as Fanconi anaemia, dyskeratosis congenita, ataxia telangiectasia
3. Inherited conditions involving defects in haematopoiesis – Down’s Syndrome
4. Acquired damage to DNA – older age, prior history of chemotherapy or radiotherapy

Learning bite: The clinical presentation of leukaemia is primarily due to the replacement of normal functioning bone marrow tissue with diseased leukaemic cells, and the subsequent failure in the production of normal blood cells⁴.